Novel 2, 3 - benzodiazepine derivatives and pharmaceutical compositions containing the same as the active ingredient

ABSTRACT

The invention refers to novel 2,3-benzodiazepine derivatives of formula (I) and pharmaceutical compositions containing the same as the active ingredient. The novel compounds antipasmodic, muscle relaxant and neuroprotective activities. In formula I; X represents a hydrogen atom, a chloro atom or a methoxy group; Y stands for a hydrogen atom or a halo atom; Z means a methyl group or a chloro atom; R is a C 1-4  alkyl group or a group of the formula —NR 1 R 2 , wherein R 1  and R 2  represent, independently, a hydrogen atom, a C 1-4  alkyl group, a C 1-4  alkoxy group or a C 3-6  cycloalkyl group.

FIELD OF THE INVENTION

[0001] The invention refers to novel 2,3-benzodiazepine derivatives andpharmaceutical compositions containing the same as the activeingredient. Due to their non-competitive AMPA antagonist effect, thenovel compounds have antispasmodic, muscle relaxant and neuroprotectiveactivities.

BACKGROUND OF THE INVENTION

[0002] The most important stimulant neurotransmitter of the centralnervous system consists of glutamic acid. The neurotransmitter receptorsof glutamic acid can be divided into two groups: ionotropic receptors(i.e. receptors connected with an ionic channel) and metabotropicreceptors. The ionotropic receptors take part in nearly each process ofthe central nervous system, for example in the processes of learning, inany type of memory, in processes accompanied by acute and chronicneuro-degeneration (or cellular destruction). The ionotropic receptorshave role in pain sense, motoric function, urination reflex andcardiovascular homeostasis, too.

[0003] Two types of ionotropic stimulant receptors exist: the NMDA andthe AMPA/kainate receptors. The receptors of AMPA/kainate type are,primarily, responsible for the so called fast synaptic processes, whilethe NMDA receptors regulate the slow synaptic processes prepared by thefast synaptic ones. Thus, antagonists of the AMPA/kainate receptors mayhave an indirect influence on the function of the NMDA receptors.Consequently, several processes of the central nervous system and thewhole organism can be regulated by the antagonists of the AMPA/kainatereceptors.

[0004] Two types of AMPA/kainate receptor antagonists exist: competitiveand non-competitive antagonists. Because of the different character ofinhibition, non-competitive antagonists are preferred to the competitiveantagonists. The first representative of the non-competitive antagonistswas 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepinesynthetized about 15 years ago. Since the discovery of this compoundnumerous 2,3-benzodiazepines having non-competitive AMPA/kainate effecthave been prepared [Donevan, S. D. et al., J. Pharmacol. Exp. Ther.,271, 25-29 (1994); Vizi, E. S. et al., CNS Drug Reviews, 2, 91-126(1996)].

[0005] The therapeutical use of 2,3-benzodiazepines havingnon-competitive antagonist effect on the AMPA/kainate receptor isextremely various. They can be employed as a neuroprotective agent incase of different acute and chronic symptoms accompanied byneurodegeneration (Parkinson's disease, Alzheimer's disease, strokeetc.), furthermore for the improvement of many symptoms e.g. inepilepsy, spasmolysis, relief of pain, influencing emesis,schizophrenia, migraine and also as an anxiolytic agent [Tarnawa, I. andVizi, E. S., Restorative Neurol. Neurosci., 13, 41-57 (1998)].

[0006] The Hungarian Patent Application No. P 97 00688 and thecorresponding GB-P No. 2 311 779 described, among others,1-(4-aminophenyl)-3-alkanoyl-4-methyl-3H-2,3-benzodiazepine derivativesthat might have contained also a chloro atom in position 7 and/or 8. Theknown compounds have antispasmodic, muscle relaxant and neuroprotectiveactivity and can be used for the treatment of neurological andpsychiatric disorders.

[0007] The scope of compounds claimed in the above patent includes2,3-benzodiazepines wherein the phenyl group being in position 1contains, in addition to the amino group in position 4, also a halo atomor a C₁₋₄ alkyl group in position 3. However, such compounds have notbeen examplified, and neither the identification data, nor thebiological effect thereof have been described.

[0008] In our animal experiments it was found that during the metabolismthat took place in the animal organism after the administration of theabove known compounds, at first, the amino group being in position 4 atthe phenyl group in position 1 was acetylated. (Further on, in thedescription, it is called N-acetylation). Due to N-acetylation, thetherapeutical effect of the compounds is reduced. Since human beings canbe of fast or slow acetylator phenotype, it is difficult to determinethe proper therapeutical dose in the treatment. Therefore, the aim ofthe invention is to find 2,3-benzodiazepine derivatives characterized bydecreased rate of acetylation since in this case human beings of fastand slow acetylator phenotype, respectively, can be treated withessentially the same dose of active ingredient.

SUMMARY OF THE INVENTION

[0009] It was found that the above aim is achieved by the novel2,3-benzodiazepine derivatives of the formula

[0010] wherein

[0011] X represents a hydrogen atom, a chloro atom or a methoxy group,

[0012] Y stands for a hydrogen atom or a halo atom,

[0013] Z means a methyl group or a chloro atom,

[0014] R is a C₁₋₄ alkyl group or a group of the formula —NR¹R², wherein

[0015] R¹ and R² represent, independently, a hydrogen atom, a C₁₋₄ alkylgroup, a C₁₋₄ alkoxy group or a C₃₋₆ cycloalkyl group,

[0016] and pharmaceutically suitable acid addition salts thereof.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] It is surprising that the above aim could be achieved by thecompounds of the invention wherein the phenyl group being in position 1contained also a methyl group or a chloro atom in ortho positionrelative to the amino group in position 4 since the ortho substitutionreduced the N-acetylation significantly. Due to the hinderedN-acetylation, some effects of the novel compounds are stronger andlonger lasting than those of the corresponding known compound in animalexperiments.

[0018] Our experiences are supported by the following experiments inwhich the undermentioned novel compounds of the formula I and thecorresponding 1-(4-aminophenyl) analogues as known reference compoundshave been used:

[0019] 1=compound of Example 1 i.e.3-acetyl-1-(4-amino-3-methyl-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,

[0020] 1a=1-(4-aminophenyl) analogue i.e.3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,

[0021] 2=compound of Example 2 i.e.1-(4-amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine,

[0022] 2a=1-(4-aminophenyl) analogue i.e.1-(4-aminophenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine,

[0023] 3=compound of Example 3 i.e.3-acetyl-1-(4-amino-3-chloro-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,

[0024] 3a=1-(4-aminophenyl) analogue i.e.3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzo-diazepine,

[0025] 4=compound of Example 4 i.e.3-acetyl-1-(4-amino-3-methyl-phenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzo-diazepine,

[0026] 4a=1-(4-aminophenyl) analogue i.e.3-acetyl-1-(4-amino-phenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzo-diazepine,

[0027] 5=compound of Example 5 i.e.1-(4-amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine,

[0028] 5a=1-(4-aminophenyl) analogue i.e.1-(4-aminophenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzo-diazepine.

[0029] Reduction of the rate of N-acetylation due to ortho substitution

[0030] Liver slices of Wistar rats were incubated in oxigenizedKrebs-Ringer solution at 37° C. in the presence of 50 μM of2,3-benzodiazepine derivative examined. 0.5 ml aliquots were taken atthe beginning of the examination, then after 30 and 60 minutes. Plasmaproteins were precipitated with perchloric acid and, after alkalization,the 2,3-benzodiazepine derivatives were extracted with chloroform. Thechloroform solutions were evaporated to dryness, the residue wasdissolved in the corresponding eluent. The 2,3-benzodiazepine derivativeused and the N-acetyl metabolite thereof were determined by highpressure liquid chromatography (Beckman System Gold HPLC, C-18reversed-phase column) using an UV detector (at 240 nm). Differenteluents were used for the optimal separation of the compounds. In caseof the compound according to Example 1 and the corresponding1-(4-amino-phenyl) analogue, the eluent consisted of a mixture of 50% of2 mM heptafluoro-butyric acid, 25% of methanol and 25% of acetonitrile.For the compound according to Example 3 and the corresponding1-(4-amino-phenyl) analogue, the eluent was a mixture of 50% of 2 mMheptafluorobutyric acid, 20% of methanol and 30% of acetonitrile. Forthe compound according to Example 4 and the corresponding1-(4-amino-phenyl) analogue, the eluent consisted of a mixture of 50% of2 mM heptafluorobutyric acid and 50% of acetonitrile.

[0031] The percentage of N-acetyl metabolite content of the sample takenat a certain time was calculated by dividing the hundredfold of the peakarea of the metabolite with the sum of the peak areas of the2,3-benzodiazepine derivative used and the N-acetyl metabolite. Theresults obtained are shown in Table 1 in which the concentrationsdetermined after 0, 30 and 60 minutes are indicated. TABLE 1 CompoundAmount of used Incubation N-acetyl (Example time in metabolite No.) min.in % 1 0 0 1 30 2 1 60 6 1a 0 0 1a 30 18 1a 60 31 3 0 0 3 30 1 3 60 1 3a0 0 3a 30 18 3a 60 31 4 0 0 4 30 0 4 60 4 4a 0 0 4a 30 17 4a 60 31

[0032] From Table 1 it can be seen that the compounds of the formula Iexamined are N-acetylated only at a negligible rate in 1 hour, incontrast to the corresponding 1-(4-aminophenyl) analogues wherein theamount of the N-acetyl metabolite is, in general, 31% in 1 hour. Thus,the presence of a methyl group or a chloro atom in ortho positionrelative to the amino group inhibits the N-acetylation of the aminogroup significantly.

Neuroprotective Effect in Magnesium Chloride Induced Global CerebralIschemia in Mice

[0033] The examination was carried out on groups consisting of 10 maleNMRI mice weighing 20-25 g. The compounds to be examined were dissolvedin a mixture of 5 volumes of 5M aqueous hydrochloric acid and 95 volumesof water, then the pH value of the solution was adjusted to 3 by theaddition of 1M aqueous sodium hydroxide solution. The solution obtainedwas administered intraperitoneally in a volume of 10 ml/kg. Eachcompound was tested at four increasing dose levels, and a further groupof animals was treated only with the vehicle (the latter was the controlgroup). 30 minutes after treatment, all mice received an intravenousinjection of saturated aqueous magnesium chloride solution in a volumeof 5 ml/kg. This injection caused an immediate cardiac arrest andcomplete cerebral ischemia. The increase in survival time (i.e. theinterval between the injection of magnesium chloride and the lastobservable gasp) was considered as a measure of the neuroprotectiveeffect according to Berga et al. [Berga, P. et al., Synergisticinteractions between piracetam and dihydroergocristine in some animalmodels of cerebral hypoxia and ischaemia, Arzneim. -Forsch., 36,1314-1320 (1986)]. Percentage changes in survival time were calculatedin comparison to that measured in the control group, and, from thevalues obtained, the dose prolonging survival by 50% (PD₅₀) wascalculated by linear regression analysis. The results obtained are shownin Table 2. TABLE 2 Compound PD₅₀, (Example No.) in mg/kg 1 4.6 1a 10.44 9.0 4a 11.0 5 12.3 5a 14.6

[0034] From Table 2 it can be seen that the PD₅₀ value of the compoundsof the formula I examined is lower than that of the corresponding1-(4-aminophenyl) analogues. This means that the substituent being inortho position relative to the amino group enhances the neuroprotectiveeffect of the compounds.

Duration of Action in Rats as Assessed From the Decrease in Body CoreTemperature

[0035] One week prior to treatments, 6 male Wistar rats wereanaesthetized by administering 60 mg/kg of pentobarbital sodium [sodium5-ethyl-5-(1-methylbutyl)barbiturate]intraperitoneally. Using sterilesurgical procedures, TL11M2C50-PXT or TA10TA-F40 type radiotelemetrytransmitters (Data Sciences International, St. Paul, Minn., USA) wereimplanted into the peritoneal cavity of the animals. The transmitterspermitted continuous monitoring of the core body temperature. Afterimplantation, the rats were treated with an antibiotic(benzathine-benzylpenicillin was administered in a dose of 1 ml/kgi.m.). [The chemical name of benzathine-benzylpenicillin:[2S-(2α,5α,6β)-3,3-dimethyl-7-oxo-6-[(phenoxyacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylicacid]. The animals were housed individually in type 2 plastic rat cageswith free access to food and tap water.

[0036] The compounds to be examined were dissolved in a mixture of 5volumes of 5M aqueous hydrochloric acid and 95 volumes of water, thenthe pH value of the solution was adjusted to 3 by the addition of 1Maqueous sodium hydroxide solution. The solution obtained wasadministered intraperitoneally in a volume of 10 ml/kg.

[0037] Radio signals emitted by the transmitters were detected byRLA1000 or RLA2000 type receivers placed under each cage. Data werecollected and saved by a Dataquest IV computerized data acquisitionsystem. The computer was set to sample body temperature for 10 secondsin every second minute. Mean values for 30 min. periods over the wholeday were calculated running the “sort utility” of the Dataquest IVsystem. The upper and lower limits of the evaluating routine were set toexclude biologically improbable values. Individual body temperaturecurves were averaged for the 6 animals.

[0038] Peak effect (PE) was measured as the maximum decrease in bodytemperature in comparison to the last value prior to treatment (controlvalue). The PE values obtained are summarized in Table 3. Using the meanvalues, duration of action (D) of the compounds was determined. This isthe time interval from treatment to return of body temperature to thecontrol level. Values of D obtained are shown in Table 4. TABLE 3Compound (Example No.) PE, Δ° C. 1 −2.34 1a 2 −2.04 2a −1.87 4 −3.09 4a−1.72

[0039] TABLE 4 Compound (Example No.) D in hour 1 20 1a 2 6 2a 4 4 19 4a3.5

[0040] From the data of Tables 3 and 4 it can be seen that the maximumdecrease in body temperature is larger and the duration of action islonger in case of the compounds containing a substituent in orthoposition relative to the amino group. This means that the effect of thecompounds of the formula I is stronger and longer lasting than that ofthe known compounds.

[0041] The compounds of the formula I have antispasmodic, musclerelaxant and neuroprotective activities, and can be potentially used inthe treatment or prevention of any disease and symptom wherein theinhibition of the stimulant amino acid receptors is beneficial. Thus,the compounds of the invention can be advantageously employed in anycase wherein the AMPA/kainate non-competitive 2,3-benzodiazepine typeantagonists are efficient, for example in the following diseases:

[0042] as a neuroprotective agent in symptoms accompanied by acute andchronic neurodegeneration, especially Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, stroke, acute head injury,furthermore for improving numerous symptoms for example in epilepsy,spasmolysis, relief of pain, in influencing emesis, in schizophrenia, incase of migraine and urination problems as well as for relieving thesymptoms of medicine deprivation.

[0043] In the description and claims, under a halo atom especially afluoro atom, chloro atom, bromo atom or iodo atom, preferably a chloroatom is meant.

[0044] A C₁₋₄ alkyl group is a methyl group, ethyl group, isopropylgroup, n-propyl group, n-butyl group, sec-butyl group, isobutyl group ortert.-butyl group, preferably a methyl group or ethyl group.

[0045] A C₁₋₄ alkoxy group is, in general, a methoxy group, ethoxygroup, isopropoxy group, n-propoxy group or n-butoxy group, preferably amethoxy group.

[0046] A C₃₋₆ cycloalkyl group is, mostly, a cyclopropyl group,cyclopentyl group or cyclohexyl group.

[0047] The pharmaceutically suitable acid addition salts of the2,3-benzodiazepine derivatives of the formula I are the non-toxic acidaddition salts of the compounds formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid etc.or organic acids such as formic acid, acetic acid, fumaric acid, lacticacid, tartaric acid, succinic acid, citric acid, benzenesulfonic acid,p-toluenesulfonic acid, methane-sulfonic acid etc.

[0048] Due to the presence of a chiral centre, the compounds of theformula I can be present in the form of optically active isomers andmixtures thereof. In the presence of certain substituents, geometricalisomerism or tautomerism may exist in the compounds of the formula I.The invention includes all the isomers of the 2,3-benzodiazepinederivatives of the formula I and any mixtures thereof.

[0049] Preferred 2,3-benzodiazepine derivatives are those wherein informula I

[0050] X represents a chloro atom,

[0051] Y stands for a hydrogen atom, a chloro atom or a bromo atom,

[0052] R means a C₁₋₄ alkyl group,

[0053] Z is a methyl group or a chloro atom,

[0054] and pharmaceutically suitable acid addition salts thereof.

[0055] The especially preferred 2,3-benzodiazepine derivatives are thosewherein in formula I

[0056] X means a chloro atom,

[0057] Y represents a hydrogen atom or a chloro atom,

[0058] R stands for a methyl group,

[0059] Z is a methyl group or a chloro atom,

[0060] and pharmaceutically suitable acid addition salts thereof.

[0061] The compounds of the formula I can be prepared by the processesknown from Hungarian Patent Application No. P 97 00688. Suitably, acompound of the formula I, wherein the amino group is replaced by anitro group, is reduced in a manner known per se, for example withtin(II) chloride, sodium dithionite or by catalytical hydrogenation inthe presence of a Raney nickel, palladium or platina catalyst usinggaseous hydrogen, hydrazine, hydrazine hydrate, formic acid, atrialkylammonium formate or a sodium formate as the hydrogen source. Thecompound of the formula I, wherein the amino group is replaced by anitro group, can be also prepared by the processes known from theHungarian Patent Application No. P 97 00688.

[0062] Furthermore, the invention refers to a pharmaceutical compositioncontaining a 2,3-benzodiazepine derivative of the formula I or apharmaceutically suitable acid addition salt thereof as the activeingredient and one or more conventional carrier(s).

[0063] The pharmaceutical composition of the invention contains, ingeneral, 0.1 to 95 per cent by mass, preferably 1 to 50 per cent bymass, suitably 5 to 30 per cent by mass of the active ingredient.

[0064] The pharmaceutical composition of the invention is suitable forperoral, parenteral or rectal administration or for local treatment, andcan be solid or liquid.

[0065] The solid pharmaceutical compositions suitable for peroraladministration may be powders, capsules, tablets, film-coated tablets,microcapsules etc., and can comprise binding agents such as gelatine,sorbitol, poly(vinylpyrrolidone) etc.; filling agents such as lactose,glucose, starch, calcium phosphate etc.; auxiliary substances fortabletting such as magnesium stearate, talc, poly(ethylene glycol),silica etc.; wetting agents such as sodium laurylsulfate etc. as thecarrier.

[0066] The liquid pharmaceutical compositions suitable for peroraladministration may be solutions, suspensions or emulsions and cancomprise e.g. suspending agents such as gelatine, carboxymethylcelluloseetc.; emulsifiers such as sorbitane monooleate etc.; solvents such aswater, oils, glycerol, propylene glycol, ethanol etc.; preservativessuch as methyl p-hydroxybenzoate etc. as the carrier.

[0067] Pharmaceutical compositions suitable for parenteraladministration consist of sterile solutions of the active ingredient, ingeneral.

[0068] Dosage forms listed above as well as other dosage forms are knownper se, see e.g. Remington's Pharmaceutical Sciences, 18th Edition, MackPublishing Co., Easton, USA (1990).

[0069] The pharmaceutical composition contains dosage unit, in general.A typical dose for adult patients amounts to 0.1 to 1000 mg of thecompound of the formula I or a pharmaceutically suitable acid additionsalt thereof calculated for 1 kg body weight, daily. The daily dose canbe administered in one or more portions. The actual dosage depends onmany factors and is determined by the doctor.

[0070] The pharmaceutical composition is prepared by admixing a compoundof the formula I or a pharmaceutically suitable acid addition saltthereof to one or more carrier(s), and converting the mixture obtainedto a pharmaceutical composition in a manner known per se. Useful methodsare known from the literature, e.g. Remington's Pharmaceutical Sciencesmentioned above.

[0071] A preferred pharmaceutical composition of the invention containsa 2,3-benzodiazepine derivative of the formula I, wherein

[0072] X represents a chloro atom,

[0073] Y stands for a hydrogen atom, a chloro atom or a bromo atom,

[0074] R means a C₁₋₄ alkyl group,

[0075] Z is a methyl group or a chloro atom,

[0076] or a pharmaceutically suitable acid addition salt thereof as theactive ingredient.

[0077] The active ingredient of an especially preferred pharmaceuticalcomposition of the invention is a 2,3-benzodiazepine derivative of theformula I, wherein

[0078] X means a chloro atom,

[0079] Y represents a hydrogen atom or a chloro atom,

[0080] R stands for a methyl group,

[0081] Z is a methyl group or a chloro atom,

[0082] or a pharmaceutically suitable acid addition salt thereof.

[0083] Furthermore, the invention refers to the use of the compounds ofthe formula I or pharmaceutically suitable acid addition salts thereoffor the preparation of a pharmaceutical composition of anxiolytic effector suitable for the treatment of symptoms accompanied by acute andchronic neurodegeneration, especially Parkinson's disease, Alzheimer'sdisease, amyotrophic lateral sclerosis, stroke, acute head injury,epilepsy and schizophrenia, for spasmolysis, relief of pain, influencingemesis, against migraine, for the treatment of urination problems or forrelieving the symptoms of medicine deprivation.

[0084] Likewise, the invention refers to a process for the treatment ofdiseases and symptoms listed above in which a therapeutically effectiveamount of a 2,3-benzodiazepine derivative of the formula I or apharmaceutically suitable acid addition salt thereof is administered toa patient being in need of the treatment.

[0085] The invention is further elucidated by means of the followingExamples.

EXAMPLE 1(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzodiazepine

[0086] 3.7 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl4-nitrophenyl)-3H-2,3-benzodiazepineare dissolved in a mixture of 75 cm³ of methanol and 38 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from ethanol. Thus, 1.67 g(49%) of the title compound are obtained in the form of pale yellowsolids melting at 180-182° C.

[0087] Analysis: for C₁₉H₂₀CIN₃O (341.844) calculated: C, 66.76%; H5.90%; N 12.29%; Cl 10.37%. found: C 66.77%; H 5.92%; N 12.13%; Cl10.13%.

[0088]¹H-NMR (CDCl₃): δ 7.48 (d, J=1.3 Hz, 1H), 7.35 (dd, J₁=2.1 Hz,J₂=8.1 Hz, 1H), 7.28 (dd, J₁=2.0 Hz, J₂=8.2 Hz, 1H), 7.22 (d, J=8.2 Hz,1H), 7.12 (d, J=2.2 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.21 (m, 1H), 4.01(bs, 2H), 2.79 (dd, J₁=5.5 Hz, J₂=13.7 Hz, 1H), 2.65 (dd, J₁=12.0 Hz,J₂=13.6 Hz, 1H), 2.20 (s, 3H), 2.02 (s, 3H), 1.30 (d, J=6.4 Hz, 3H).

[0089]¹³C-NMR (CDCl₃): δ 172.14, 169.21, 148.14, 138.46, 135.83, 132.35,131.43, 130.27, 129.40, 129.24, 128.72, 125.45, 121.79, 114.03, 60.47,38.28, 22.60, 18.32, 17.32.

EXAMPLE 2(±)-1-(4-Amino-3-methylphenyl)-4,5-dihydro-8-chloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine

[0090] 3.86 g (10 mmoles) of(±)-4,5-dihydro-8-chloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepineare dissolved in a mixture of 80 cm³ of methanol and 13 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from acetonitrile. Thus, 1.99g (56%) of the title compound are obtained in the form of cream colouredsolids melting at 152-154° C.

[0091]¹H-NMR (CDCl₃): δ 7.47 (d, J=1.1 Hz, 1H), 7.34 (dd, J₁=2.1 Hz,J₂=8.1 Hz, 1H), 7.29 (dd, J₁=2.0 Hz, J₂=8.2 Hz, 1H), 7.22 (d, J=8.2 Hz,1H), 7.10 (d, J=2.2 Hz, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.21 (m, 1H), 4.01(bs, 2H), 2.78 (dd, J₁=5.6 Hz, J₂=13.7 Hz, 1H), 2.66 (˜t, J=12.9 Hz,1H), 2.47 (m, 1H), 2.20 (m, 1H), 2.20 )s, 3H), 1.30.(d, J=6.4 Hz, 3H),1.04 (t, J=7.5 Hz, 3H).

[0092]¹³C-NMR (CDCl₃): δ 172.46, 172.20, 154.48, 148.11, 138.54, 135.94,132.27, 131.39, 130.19, 129.36, 129.19, 128.60, 125.48, 121.76, 114.03,60.58, 38.29, 27.90, 18.34, 17.33, 8.77.

EXAMPLE 3(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-8-chloro-4-methyl-3H-2,3-benzodiazepine

[0093] 3.93 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-8-chloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 30 cm³ of methanol and 30 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from a mixture of ethylacetate and hexane. Thus, 1.03 g (30%) of the title compound areobtained in the form of yellow solids melting at 143-144° C.

[0094] Analysis: for C₁₈H₁₇Cl₂N₃O (362.262) calculated: C 59.68%; H4.73%, N 11.60%; Cl 19.57%. found: C 59.09%; H 4.85%; N 11.24%; Cl19.11%.

[0095]¹H-NMR (CDCl₃): δ 7.65 (d, J=1.9 Hz, 1H), 7.35 (m, 2H), 7.23 (d,J=8.2 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 5.23 (m,1H), 4.44 (bs, 2H), 2.83 (dd, J₁=5.1 Hz, J₂=13.9 Hz, ₁ H), 2.66 (dd,J₁=11.4 Hz, J₂=13.8 Hz, 1H), 2.06 (s, 3H), 1.26 (d, J=6.4 Hz, 3H).

[0096]¹³C-NMR (CDCl₃): δ 169.88, 168.02, 145.71, 138.52, 135.15, 132.54,130.47, 130.37, 129.69, 129.27, 128.69, 126.81, 119.01, 114.88, 60.31,38.21, 22.68, 18.44.

EXAMPLE 4(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzodiazepine

[0097] 4.06 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 55 cm³ of methanol and 55 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from a mixture ofethyl acetate and hexane. Thus, 3.27 g (87%) of the title compound areobtained in the form of yellow ochre solids melting at 127-129° C.

[0098] Analysis: for C₁₉H₁₉Cl₂N₃O (376.289) calculated: C 60.65%; H5.09%; N 11.17%; Cl 18.84%. found: C 59.74%; H 5.07%; N 10.98%; Cl18.62%.

[0099]¹H-NMR (CDCl₃): δ 7.45 (˜s, 1H), 7.39 (s, 1H), 7.28 (dd, J₁=2.0Hz, J₂=8.2 Hz, 1H), 7.22 (s, 1H), 6.77 (d, J=8.3 Hz, 1H), 5.23 (m, 1H),4.02 (bs, 2H), 2.77 (dd, J₁=5.5 Hz, J₂=13.8 Hz, 1H), 2.65 (dd, J₁=11.8Hz, J₂=13.5 Hz, 1H), 2.20 (s, 3H), 2.03 (s, 3H), 1.29 (d, J=6.4 Hz, 3H).

[0100]¹³C-NMR (CDCl₃): δ 169.40, 148.25, 139.93, 134.23, 134.08, 131.42,130.73, 130.56, 129.93, 129.15, 125.24, 121.86, 114.09, 60.07, 38.10,22.60, 13.80, 17.32.

EXAMPLE 5(±)-1-(4-Amino-3-methylphenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3-propionyl-3H-2,3-benzodiazepine

[0101] 4.2 g (10 mmoles) of(±)-4,5-dihydro-7,8-dichloro-4-methyl-1-(3-methyl-4-nitrophenyl)-3-propionyl-3H-2,3-benzodiazepineare dissolved in a mixture of 40 cm³ of methanol and 40 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by chromatography over acolumn containing silica gel and using a mixture of ethyl acetate andhexane, then the product is recrystallized from acetonitrile. Thus, 1.99g (56%) of the title compound are obtained in the form of pale yellowsolids melting at 106-108° C.

[0102] Analysis: for C₂₀H₂₁Cl₂N₃O (390.316) calculated: C 61.55%; H5.42%; N 10.77%; Cl 18.17%. found: C 60.68%; H 5.52%; N 10.47%; Cl17.90%.

[0103]¹H-NMR (CDCl₃): δ 7.45 (d, J=1.1 Hz, 1H), 7.39 (s, 1H), 7.28 (dd,J₁=2.1 Hz, J₂=8.3 Hz, 1H), 7.21 (s, 1H), 6.67 (d, J=8.3 Hz, 1H), 5.22(m, 1H), 4.02 (bs, 2H), 2.77 (dd, J₁=5.6 Hz, J₂=13.8 Hz, 1H), 2.64 (dd,J₁=11.9 Hz, J₂=13.6 Hz, 1H), 2.47 (m, 1H), 2.20 (m, 1H), 2.20 (s, 3H),1.30 (d, J=6.4 Hz, 3H), 1.04 (t, J=7.5 Hz, 3H).

[0104]¹³C-NMR (CDCl₃): δ 172.63, 171.10, 148.22, 140.02, 134.20, 131.40,130.66, 130.44, 129.90, 129.12, 125.28, 121.86, 114.10, 60.21, 38.12,27.92, 18.32, 17.34, 8.77.

EXAMPLE 6(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-7,8-dichloro-4-methyl-3H-2,3-benzodiazepine

[0105] 4.26 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7,8-dichloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 40 cm³ of methanol and 40 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from acetonitrile.Thus, 2.80 g (71%) of the title compound are obtained in the form ofbutter coloured solids melting at 127-129° C.

[0106] Analysis: for C₁₈H₁₆C₁₃N₃O (396.707) calculated: C 54.50%; H4.07%; N 10.59%; Cl 26.81%. found: C 54.26%; H 4.14%; N 10.48%; Cl26.28%.

[0107]¹H-NMR (CDCl₃): δ 7.62 (d, J=1.9 Hz, 1H), 7.39 (s, 1H), 7.32 (dd,J₁=2.0 Hz, J₂=8.4 Hz, 1H), 7.22 (s, 1H), 6.77 (d, J=8.4 Hz, 1H), 5.25(m, 1H), 4.48 (bs, 2H), 2.82 (dd, J₁=5.1 Hz, J₂=13.9 Hz, 1H), 2.66 (dd,J₁=11.2 Hz, J₂=13.8 Hz, 1H), 2.07 (s, 3H), 1.25 (d, J=6.4 Hz, 3H).

[0108]¹³C-NMR (CDCl₃): δ 170.03, 166.60, 145.80, 139.93, 134.45, 133.34,130.88, 130.52, 130.29, 130.18, 129.17, 126.53, 119.00, 114.88, 59.79,37.99, 22.68, 18.42.

EXAMPLE 7(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

[0109] 4.46 g (10 mmoles) of(±)-3-acetyl-7-bromo4,5-dihydro-1-(3-methyl-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepineare dissolved in 190 cm³ of methyl cellosolve, then 2.1 g (15 mmoles) ofpotassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and,under vigorous stirring, 1.95 cm³ (40 mmoles) of 98% hydrazine hydrateare added. The reaction mixture is stirred at 100° C. for 1 hour, thecatalyst is filtered, the filtrate is evaporated, and the residue isrubbed with 50 cm³ of water to obtain solid matter. The crude product ispurified by chromatography over a column containing silica gel and usinga mixture of ethyl acetate and hexane, then the product isrecrystallized from acetonitrile. Thus, 1.6 g (47%) of the titlecompound are obtained in the form of cream coloured solids melting at169-171° C.

[0110] Analysis: for C₂₀H₂₃N₃O₂ (337.425) calculated: C 71.19%; H 6.87%;N 12.45%. found: C 71.69%; H 6.74%; N 12.34%.

[0111]¹H-NMR (CDCl₃): δ 67.51 (bs, 1H), 7.33 (dd, J₁=1.8 Hz, J₂=8.1 Hz,1H), 7.19 (d, J=8.4 Hz, 1H), 6.91 (dd, J₁=2.9 Hz, J₂=8.4 Hz, 1H), 6.65(d, J=8.1 Hz, 1H), 6.65 (d, J=2.6 Hz, 1H), 5.18 (m, 1H), 3.97 (bs, 2H),2.72 (m, 1H), 2.61 (m,1H), 2.19 (s, 3H), 2.01 (s, 3H), 1.31 (d, J=6.6Hz, 3H).

[0112]¹³C-NMR (CDCl₃): δ 168.89, 158.06, 147.91, 135.19, 132.25, 131.59,129.36, 129.02, 125.98, 121.67, 115.67, 114.79, 114.00, 60.69, 55.49,38.03, 22.59, 18.32, 17.29.

EXAMPLE 8(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

[0113] 4.66 g (10 mmoles) of(±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzo-diazepineare dissolved in 190 cm³ of methyl cellosolve, then 2.1 g (15 mmoles) ofpotassium carbonate and 1.8 g of 10% palladium/charcoal catalyst and,under vigorous stirring, 1.95 cm³ (40 mmoles) of 98% hydrazine hydrateare added. The reaction mixture is stirred at 90 ° C. for 0.5 hours, thecatalyst is filtered, the filtrate is evaporated, and the residue isrubbed with 50 cm³ of water to obtain solid matter. The crude product ispurified by chromatography over a column containing silica gel and usinga mixture of ethyl acetate and hexane, then the product isrecrystallized from ethanol. Thus, 1.1 g (30%) of the title compound areobtained in the form of white solids melting at 152-155° C.

[0114] Analysis: for C₁₉H₂₀CIN₃O₂ (357.840) calculated: C 63.77%; H5.63%; N 11.74%; Cl 9.91%. found: C 63.70%; H 5.61%; N 11.51%; Cl 9.86%.

[0115]¹H-NMR (CDCl₃): δ 7.67 (d, J=1.8 Hz, 1 H), 7.41 (dd, J₁=1.8 Hz,J₂=8.1 Hz, 1H), 7.20 (d, J=8.4 Hz, 1 H), 6.93 (dd, J₁=2.6 Hz, J₂=8.1 Hz,1H), 6.77 (d, J=8.4 Hz, 1H), 6.64 (d, J=2.9 Hz, 1H), 5.20 (m, 1H), 4.46(bs, 2H), 3.75 (s, 3H), 2.80 (dd, J₁=5.1 Hz, J₂=13.9 Hz, 1H), 2.63 (dd,J₁=11.7 Hz, J₂=13.9 Hz, 1H), 2.05 (s, 3H), 1.29 (d, J=6.2 Hz, 3H).

[0116]¹³C-NMR (CDCl₃): δ 158.12, 145.56, 134.48, 132.25, 130.55, 129.38,129.28, 118.86, 115.84, 114.80, 114.68, 60.66, 55.49, 37.91, 22.67,18.42.

EXAMPLE 9(±)-3-Acetyl-1-(4-amino-3-methylphenyl)-4,5-dihydro-7-chloro-4-methyl-3H-2,3-benzodiazepine

[0117] 3.7 g (10 mmoles) of(±)-3-acetyl-4,5-dihydro-7-chloro-1-(3-methyl-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepineare dissolved in a mixture of 80 cm³ of methanol and 33 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is recrystallized from a 1:2 mixture ofethyl acetate and hexane. Thus, 2.88 g (84%) of the title compound areobtained in the form of yellow ochre solids melting at 200-205° C.

[0118] Analysis: for C₁₉H₂₀ClN₃O (341.844) calculated: C 66.76%; H5.90%; N 12.29%; Cl 10.37%. found: C 65.63%; H 6.07%; N 12.03%; Cl10.58%.

[0119]¹H-NMR (CDCl₃): δ 7.45 (s, 1H), 7.28 (m, 3H), 7.07 (d, J=8.2 Hz,1H), 6.66 (d, J=8.2 Hz, 1H), 5.24 (m, 1H), 4.00 (bs, 2H), 2.77 (dd,J₁=5.6 Hz, J₂=13.7 Hz, 1H), 2.68 (t, J=12.8 Hz, 1H), 2.18 (s, 3H), 2.01(s, 3H), 1.31 (d, J=6.3 Hz, 3H).

[0120]¹³C-NMR (CDCl₃): δ 172.54, 169.11, 148.08, 141.85, 136.09, 132.62,131.54, 130.32, 129.16, 128.22, 126.63, 125.68, 121.69, 114.00, 60.30,38.67, 22.55, 18.34, 17.29.

EXAMPLE 10(±)-3-Acetyl-1-(4-amino-3-chlorophenyl)-7-bromo4,5-dihydro-4-methyl-8-methoxy-3H-2,3-benzodiazepine

[0121] 4.66 g (10 mmoles) of(±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepineare dissolved in a mixture of 45 cm³ of methanol and 45 cm³ ofdichloromethane, then 3.0 g of wet Raney nickel catalyst and, undervigorous stirring, 1.7 cm³ (35 mmoles) of 98% hydrazine hydrate areadded. The reaction mixture is stirred for further 45 minutes, thecatalyst is filtered, washed with dichloromethane, the filtrate isevaporated, and the residue is rubbed with 50 cm³ of water to obtainsolid matter. The crude product is purified by boiling in 50 ml ofacetonitrile. Thus, 3.52 g (81%) of the title compound are obtained inthe form of white solids melting at 235-237° C.

[0122] Analysis: for C₁₉H₁₉BrCIN₃O₂ (436.740) calculated: C 52.25%; H4.39%; N 9.62%; ΣHIg(Cl) 16.24%. found: C 51.04%; H 4.34%; N 9.39%;ΣHIg(Cl) 16.16%.

[0123]¹H-NMR (CDCl₃): δ 7.65 (d, J=1.8 Hz, 1H), 7.48 (s, 1H), 7.36 (dd,J₁=1.8 Hz, J₂=8.3 Hz, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 5.21(m, 1H), 4.46 (bs, 2H), 3.77 (s, 3H), 2.77 (dd, J₁=5.1 Hz, J₂=14.1 Hz,1H), 2.62 (dd, J₁=11.4 Hz, J₂=13.9 Hz, 1H), 2.07 (s, 3H), 1.25 (d, J=6.3Hz, 3H).

[0124]¹³C-NMR (CDCl₃): δ169.77, 168.18, 154.48, 145.64, 133.71, 133.50,133.04%, 130.45, 129.25, 126.94, 118.89, 114.81, 114.08, 112.42, 60.48,56.52, 37.54, 22.74, 1843.

1. A 2,3-benzodiazepine derivative of the formula

wherein, X represents a hydrogen atom, a chloro atom or a methoxy group,Y stands for a hydrogen atom or a halo atom, Z means a methyl group or achloro atom, R is a C₁₋₄ alkyl group or a group of the formula —NR¹R²,wherein R¹ and R² represent, independently, a hydrogen atom, a C₁₋₄alkyl group, a C₁₋₄ alkoxy group or a C₃₋₆ cycloalkyl group, andpharmaceutically suitable acid addition salts thereof.
 2. A2,3-benzodiazepine derivative according to claim 1, wherein X representsa chloro atom, Y stands for a hydrogen atom, a chloro atom or a bromoatom R means a C₁₋₄ alkyl group, Z is as defined in claim 1, andpharmaceutically suitable acid addition salts thereof.
 3. A2,3-benzodiazepine derivative according to claim 2, wherein Y representsa hydrogen atom or a chloro atom, R stands for a methyl group, X and Zare as defined in claim 2, and pharmaceutically suitable acid additionsalts thereof.
 4. A pharmaceutical composition comprising a2,3-benzodiazepine derivative of the formula I, wherein X, Y, Z and Rare as defined in claim 1, or a pharmaceutically suitable acid additionsalt thereof as the active ingredient in addition to the usualcarrier(s).
 5. A pharmaceutical composition according to claim 4comprising a 2,3-benzodiazepine derivative of the formula I, wherein X,Y, Z and R are as defined in claim 2, or a pharmaceutically suitableacid addition salt thereof as the active ingredient.
 6. A pharmaceuticalcomposition according to claim 5 comprising a 2,3-benzodiazepinederivative of the formula I, wherein X, Y, Z and R are as defined inclaim 3, or a pharmaceutically suitable acid addition salt thereof asthe active ingredient.
 7. Use of a 2,3-benzodiazepine derivative of theformula I, wherein X, Y, Z and R are as defined in claim 1, or apharmaceutically suitable acid addition salt thereof, for thepreparation of a pharmaceutical composition of anxiolytic effect orsuitable for the treatment of symptoms accompanied by acute and chronicneurodegeneration, especially Parkinson's disease, Alzheimer's disease,amiotrophic lateral sclerosis, stroke, acute head injury, epilepsy andschizophrenia, for spasmolysis, influencing emesis, against migraine,for the treatment of urination problems or for relieving the symptoms ofmedicine deprivation.
 8. A process for the treatment of diseases andsymptoms according to claim 7 characterized by administering atherapeutically effective amount of a 2,3-benzodiazepine derivative ofthe formula I, wherein X, Y, Z and R are as defined in claim 1, or apharmaceutically suitable acid addition salt thereof to a patient beingin need of the treatment.